Photosensitive pro-drug nanoassemblies harboring a chemotherapeutic dormancy function potentiates cancer immunotherapy

Immunotherapy combined with effective therapeutics such as chemotherapy and photodynamic therapy have been shown to be a successful strategy to activate anti-tumor immune responses for improved anticancer treatment. However, developing multifunctional biodegradable, biocompatible, low-toxic but highly efficient, and clinically available transformed nano-immunostimulants remains a challenge and is in great demand. Herein, we report and design of a novel carrier-free photo-chemotherapeutic nano-prodrug COS-BA/Ce6 NPs by combining three multifunctional components-a self-assembled natural small molecule betulinic acid (BA), a water-soluble chitosan oligosaccharide (COS), and a low toxic photosensitizer chlorin e6 (Ce6)-to augment the antitumor efficacy of the immune adjuvant anti-PD-L1-mediated cancer immunotherapy. We show that the designed nanodrugs harbored a smart and distinctive "dormancy" characteristic in chemotherapeutic effect with desired lower cytotoxicity, and multiple favorable therapeutic features including improved 1O2 generation induced by the reduced energy gap of Ce6, pH-responsiveness, good biodegradability, and biocompatibility, ensuring a highly efficient, synergistic photochemotherapy. Moreover, when combined with anti-PD-L1 therapy, both nano-coassembly based chemotherapy and chemotherapy/photodynamic therapy (PDT) could effectively activate antitumor immunity when treating primary or distant tumors, opening up potentially attractive possibilities for clinical immunotherapy.

Efficacy and Safety of Pidotimod in Persistent Asthma: A Randomized Triple-Blinded Placebo-Controlled Trial

Objective: To study whether addition of pidotimod to inhaled corticosteroid (ICS) therapy enhances control in children with persistent asthma, as compared to ICS therapy alone. Design: Triple-blinded, randomized controlled trial. Setting: Allergy and Asthma Clinic, Department of Pediatrics, at a tertiary care hospital between May, 2018 and June, 2019. Patients: 79 children (5-12 years) with newly diagnosed persistent asthma as per Global Initiative for Asthma guidelines. Interventions: Children received 7 mL twice-a-day for 15 day, followed by 7 mL once-a-day for 45 days of either pidotimod (n=39) or placebo (n=40). In addition, both groups received inhaled budesonide via metered dose inhaler and spacer, throughout the study. Children were followed up every 4 weeks for a total of 12 weeks. At each follow-up visit, peak expiratory flow (PEF) and asthma symptom score and medicine adverse effects were recorded. Main outcome measures: Change in PEF at 12 weeks compared to baseline. Secondary outcomes were PEF at each follow-up visit, asthma symptom score at each visit, change in asthma symptom score at 12 weeks, and adverse event profile. Results: The median (IQR) change in PEF (from baseline to 12 weeks) was 13.0% (0.8%, 28.3%) in pidotimod group (n=35) vs 17.7% (4.3%, 35.2%) in placebo group (n=35) (P=0.69). All the secondary outcomes were also comparable between the two groups. There were no significant adverse effects observed. Conclusions: Addition of pidotimod for 8 weeks to standard ICS therapy did not enhance asthma control compared to placebo.

Immunomodulatory effects of dietary ß-glucan in silver catfish (Rhamdia quelen) / Efeito imunomodulador da ß-glucana usada como aditivo alimentar em jundiás (Rhamdia quelen)

The immunomodulatory effects of dietary ß-glucan were evaluated in silver catfish. ß-glucan was added to the diet (0.01%, and 0.1%) and fed to the fish for 21 days, to evaluate effects on blood and some innate immune parameter, or fed for 42 days, to evaluate growth rate and resistance to challenge with pathogenic Aeromonas hydrophila. We found that adding ß-glucan to the diet had no effect on fish growth and no effect on blood cells, or serum bacterial agglutination and serum myeloperoxidase activity. However, fish that received ß-glucan in the diet had the natural hemolytic activity of complement significantly higher compared to control fish. Furthermore, fish fed with ß-glucan and challenged with A. hydrophila had fewer bacteria in blood and presented a significantly higher survival rate compared to control fish. Thus, we concluded that ß-glucan might be explored as feed additive aiming to improve silver catfish innate immunity and resistance to specific pathogen.(AU)

O uso da ß-glucana como suplemento alimentar foi avaliado em jundiás. A ß-glucana foi adicionada à ração na proporção de 0.01%, e 0.1% e fornecida aos peixes por 21, para avaliar dados hematológicos e parâmetros do sistema imune natural, ou 42 dias, para avaliar ganho de peso e resistência ao desafio com Aeromonas hydrophila. A adição da ß-glucana na dieta não afetou o ganho de peso e não induziu alterações hematológicas nem alterações nos níveis de aglutininas e mieloperoxidase sanguínea. No entanto, a atividade hemolítica natural do sistema do complemento foi significativamente maior nos peixes alimentados com ß-glucana. Além disso, nos peixes alimentados com ß-glucana e desafiados com A. hydrophila, o número de bactérias isoladas do sangue foi significativamente menor, e a sobrevivência ao desafio foi significativamente maior do que nos peixes que não receberam ß-glucana. Consequentemente, concluímos que a ß-glucana tem potencial imunomodulador quando adicionada à dieta, nas condições experimentais aqui indicadas, e contribui para aumentar imunidade natural e a resistência dos jundiás ao desafio com patógenos específicos.(AU)

Carissa congesta Wight and Benincasa hispida (Thunb.) Cogn. as budding immunomodulatory agents.

Carissa congesta and Benincasa hispida are well-known medicinally important plants associated with diabetes, inflammation, protozal infections and cancer. Here, we emphasized up on the immunomodulatory potential of these plants as the source of lupeol, β-sitosterol and ursolic acid. Petroleum ether extracts of C. congesta roots and B. hispida seeds were subjected to acute toxicity studies. They were screened for its immunomodulatory prospective in rats by Haemagglutination Antibody (HA) titre and Delayed-Type Hypersensitivity (DTH) response using Sheep Red Blood Cells (SRBCs of-0.5×109) as antigens. Carbon Clearance test (Phagocytic Index) was estimated by Indian ink suspension. Complete Freund’s Adjuvant (CFA) induced arthritis model interpretation was done by paw edema, kene joint erosion (transverse section), body weights, arthritic index and biochemical levels (RBC, WBC and Hb levels). Both the extracts were found to be therapeutically safe up to 5000 mg/kg. Dosage of 100 mg/kg was not satisfactory; and 500 and 250 mg/kg showed significant immunostimmulation (HA Titre) and immunosuppression (DTH response, 48 h). Benincasa hispida seed and Carissa congesta root extracts showed phagocytic Index of 0.0163±0.003, 0.0145±0.003 and 0.0183±0.003, 0.0176±0.003 at 250 mg/kg and 500 mg/kg, respectively. CFA model revealed that the B. hispida seed and C. congesta root extracts decreased paw volume, knee joint erosion, increased body weights and biochemical parameters with an arthritic index of 1.31±0.12, 1.44±0.15 and 1. 16±0.09, 1.36±0.13 at 250 mg/kg and 500 mg, respectively. The results were interpreted by One-way ANOVA followed by Dunnett test. Extracts showed relevance as promising immunostimulators as compared to control.

Effcets on immunoregulation of iNKT cells in RA by novel synthetic immunos-timulator CH1 b / 中国免疫学杂志

Objective:To investigate effects of a novel synthetic immunostimulator CH1b containing thiazolidin-4-one on the immunoregulation funotion of iNKT ( invariant nature killer T ) cells in active RA patients in vitro.Methods: Peripheral blood mononuclear cells( PBMCs) isolated from active RA patients were cultured with stimulation of α-Galcer and IL-2 in vitro and iNKT cells were then separated by using magnetic activated cell sorting( MACS) method with iNKT isolation kit.The cells were divided into three groups:control group (IL-2),α-Galcer group (IL-2+α-Galcer),CH1b group(IL-2 +CH1b).The effects of CH1b on the proliferation of iNKT cells in active RA patients were analyzed by using MTT assay.MILLIPLEX MAP Human Cytokine/Chemokine kit was used to evaluate the secretion of IFN-γand IL-4 in iNKT cells culture media.The expressions of IFN-γmRNA and IL-4 mRNA in iNKT cells were analyzed by RT-PCR.Results: Compared with control and α-Galcer group,the proliferation of iNKT cells of CH1b group were significantly higher( P<0.05).Compared with control,the ratio of IFN-γ/IL-4 in iNKT cells culture media in active RA patients of CH1b group were significantly lower (P<0.05).Compared with control,expressions of IFN-γmRNA and IL-4 mRNA were higher inα-Galcer group;compared with control,expressions of IL-4 mRNA were higher in CH1b group,while there were no obvious difference on expressions of IFN-γmRNA.Conclusion:CH1b was found to significantly stimulate the actived iNKT cells in active RA patients proliferation,promote the secretion of IL-4,and increase the ratio of IFN-γ/IL-4,promote the expression of IL-4 mRNA in iNKT cells in active patients.

Effects of C-pseudonucleosides bearing thiazolidin-4-one as immunostimulants on differentiations of human lymphocytes / 中华微生物学和免疫学杂志

Objective To explore the effects of C-pseudonucleosides bearing thiazolidin-4-one as immunostimulants on differentiation and activation of human lymphocytes. Methods Peripheral blood mononuclear cells (PBMC) were isolated from healthy adults,and then incubated with immunostimulants (CH1a,CH2a,CH1b,CH2b and pidotimod).After 48 h,we collected the supernatants and then detected the concentrations of IL-2,IL-4 and IFN-γ using ELISA.After 72 h,the proliferation was detected using MTT method.PBMC incubated with immunostimulants (CH1a,CH2a,CH1b,CH2b and pidotimod),after 72 h,the cultural cells were collected and CD expressions of lymphocytes were analyzed by flow cytometry.Results All samples could stimulate proliferation of T cells.Immunostimulants CH1a,CH2a and pidotimod could elevate the expressions of CD3,CD4,CD19 and CD16CD56,and stimulate the secretions of IL-2 and IFN-γ. Immunostimulants CH1b and CH2b could elevate the expressions of CD3,CD4,CD19 and CD16CD56,and stimulate the secretions of IL-2 and IL-4. Conclusion Immunostimulants CH1a and CH2a could differentiate Th0 into Th1 and promote the proliferation of B cells as well as NK cells.However,immunostimulants CH1b and CH2b could differentiate Th0 into Th2 and promote the proliferation of B cells and NK cells.